Photodynamic therapy for photoaging and effects on skin barrier

The exogenous aging of the skin is mainly caused by long-term sun exposure, also known as skin photoaging. The clinical manifestations are skin aging appearance such as rough skin, deep wrinkles, pigmentation and telangiectasia. Skin aging is often accompanied by barrier dysfunction of the skin. The skin barrier consists of a water-lipid membrane and a “brick wall”-like structure that isolates and protects the epidermis and dermis, and plays an important role in maintaining the stability of the body’s environment. A variety of skin diseases such as atopic dermatitis, psoriasis, Contact dermatitis and the like are all related to the stability of the skin barrier function. Previous studies have found that photodynamic therapy can treat and prevent photoaging in addition to skin tumors, condyloma acuminata and hemorrhoids, and also has an effect on skin barrier function. This article will be elaborated from two levels of clinical and institutional research.

1. Photoaging and skin barrier

Skin aging is divided into endogenous aging and exogenous aging. The former refers to the natural aging of the skin with age, while the latter refers to the skin aging caused by external environmental factors. Because the long-term repeated exposure of ultraviolet light in sunlight is the most important factor affecting skin aging in the environment, exogenous aging Also known as photoaging. Photoaging skin is mainly characterized by loose skin, roughness, wrinkles, pigmentation and telangiectasia, which not only affects the appearance but also develops precancerous lesions and skin tumors. At the histological level, epidermal atrophy of photoaged skin with thinning of the spinous layer or thickening of the epidermis with acanthosis, flattening of the true epidermal junction, disappearance of the epidermal process; the most characteristic change is the degenerative structure of the dermal collagen Change: The content of collagen I, which is the most abundant in the dermis, is reduced, resulting in decreased skin toughness, weakened tensile strength, and inability to maintain full filling. Type I collagen and elastic fiber degeneration, abnormal thickening, curling, amorphous elastin Deposition of the sample material causes the skin to lose its original elasticity and compliance, resulting in slack and wrinkles. Therefore, against the skin photoaging, heavy plastic original structure is the most important purpose.
The generalized skin barrier function includes physical barriers, pigment barriers, neural barriers, barriers and other barriers related to skin function. This article refers to the narrow skin barrier, usually refers only to physical or mechanical barrier structures, and is composed of water. Lipid membranes and keratinocytes are composed of a “brick wall”-like structure composed of intercellular lipids. The outermost line of defense of the skin barrier structure is a water-lipid film. The lipids not only lubricate the skin, but also reduce the evaporation of water. The natural moisturizing factor contained in the water-fat film also has an important water-holding function. Keratinocytes are “bricks” in the “brick wall”-like structure of the skin barrier. The cytoplasmic keratin bundles in the cytoplasm are dense and solid, and the insoluble keratinous envelopes together perform their barrier function. As a “mortar” between bricks, intercellular lipids have a typical lipid bilayer membrane structure and are a powerful barrier for substances to enter and exit the epidermis.
On the one hand, the skin barrier protects the skin from external unfavorable factors, and on the other hand prevents the loss of water, nutrients and electrolytes in the skin and the body, helping to maintain the relative stability of the body environment. Skin barrier function damage is manifested in decreased water content in the stratum corneum, increased transepidermal water loss (TEWL), altered p H values, and abnormal skin lipid content and composition. Impaired skin barrier function can cause dry skin, skin aging, atopic dermatitis, psoriasis, solar dermatitis and other skin diseases. Acute UV exposure can impair the barrier function of the skin, causing severe damage to the keratinocyte strain, cohesion and mechanical integrity, thereby destroying the skin barrier function. Chronic ultraviolet radiation can reduce the water content of the stratum corneum of the skin, and the loss of transepidermal water increases, resulting in impaired barrier function of photoaged skin. The basal layer of keratinocytes in naturally aging skin is weakened, resulting in thinning of the epidermis, flattening of the epidermal junction, and short epidermal changes. This epidermal change also occurs in photoaged skin. The flattening of the true epidermal connection reduces the contact area of ​​the true epidermis, reduces the exchange of nutrients between the true epidermis, and affects the proliferation and activity of the keratinocytes, which indirectly affects the skin barrier function. The water content of the stratum corneum of naturally aging skin is slightly reduced or maintained, the transepidermal water loss is unchanged, the sebum content is reduced, and the photoaging skin may also have a similar skin barrier function change. Damage to the skin barrier also accelerates skin aging. Thus, impaired skin barrier function and photoaging of the skin usually occur simultaneously and are mutually reinforcing factors.

2. Clinical study of photodynamic therapy affecting photoaging and skin barrier

Photodynamic therapy (PDT) is a new combination of photosensitizers and corresponding light sources that selectively destroy diseased tissue with photodynamic effects in the presence of oxygen. It is used in dermatology for precancerous lesions and skin. Treatment of diseases such as tumors, genital warts, and hemorrhoids. In 2002, Ruiz-Rodrfguez et al. first proposed the concept of photodynamic skin rejuvenation. In 2010, Bruscino et al first reported that photodynamic therapy has a skin rejuvenation effect in the treatment of solar keratosis. Subsequently, several studies have confirmed that photodynamic therapy has improved collagen structure abnormalities in photoaging skin, and different skin rejuvenation effects are different. Microneedle pretreatment can enhance the photoaging aging effect of photodynamics. Since skin photoaging and skin barrier function damage often occur simultaneously, skin barrier repair is the basis for the treatment of photoaging and other light-induced skin diseases. A number of studies have shown that photodynamic therapy improves skin photoaging while also improving skin barrier function.
The classic photodynamic therapy uses 635nm red light as the light source, which penetrates deeper and is consistent with the absorption peak of protoporphyrin IX. Red light itself also has a certain skin rejuvenation effect. Ji et al. performed a comparative study of red light-photodynamics and simple red light treatment on the forearm stretch-photoaging skin. The results showed that both photodynamic and simple red light caused histological collagen disorder and elastic fiber degeneration to be improved histologically; Compared with the simple red light group, the appearance of photoaging skin lesions in the red-photodynamic group was more significantly improved, and the water content of the stratum corneum was more significantly increased, and the reduction of transepidermal water loss was more significant, indicating Compared with photodynamic therapy, pure red light treatment not only has better skin rejuvenation effect, but also can improve skin barrier function to a greater extent.
Intense pulsed light (IPL) is a commonly used skin rejuvenation source with a wavelength ranging from 500 nm to 1200 nm, covering the absorption peak of PpIX. It is an ideal therapeutic light source for photodynamic therapy. Zhang Haiyan and other zoning studies on photoaging skin of the neck showed that the photodynamic group and the pure IPL and red light groups improved in skin brightness, elasticity and thickness, and the melanin index decreased, and the improvement of these indicators was in the photodynamic group. More obvious; after 12 weeks of treatment, IPL-photodynamic therapy of photoaging skin continued to increase the water content of the stratum corneum, and the transepidermal water loss continued to decrease, while the red-photodynamic treatment area showed a transient at the beginning of follow-up. Decreased water content in the stratum corneum and increased percutaneous water loss may reflect skin barrier damage caused by side effects such as erythema and edema. Both indicators were superior to pre-treatment levels in the late follow-up period, suggesting that photodynamic therapy ultimately has a beneficial effect on the skin barrier. Although the skin barrier was also associated with sebum levels, the study did not detect a meaningful change in the level of sebum after photodynamic therapy. The results of the half-face control experiment conducted by Yang et al showed that the photoaging score of IPL-photodynamic therapy group was lower than that of IPL group, and the up-regulation of p H value and water content of stratum corneum in forehead and corner skin were better than Significantly in the IPL-treated group, IPL-photodynamic therapy improved skin barrier function while treating photoaging, and its effect was more pronounced than IPL alone.
Gold and other studies have shown that short-term (30-60min) IPL-photodynamic therapy improves the photoaging lesions more than the IPL alone, and is superior to crow’s feet, pigmentation, roughness, and telangiectasia. IPL treatment alone, and clearance rate for solar keratosis lesions is also higher. In addition, Clementoni et al. pretreated the skin of the 21 patients with microneedle rollers before the application, and irradiated with red light and IPL light source. The photoaging scores were evaluated at 3 months and 6 months after treatment. And 90% of patients had a greater than 50% improvement in clinical improvement at 6 months after treatment compared with pre-treatment. It indicates that the microneedle roller pretreatment has good tolerance, which can enhance the absorption and penetration of ALA on the skin and improve the clinical efficacy.
The discomfort of photodynamic therapy mainly comes from adverse reactions such as pain, erythema, edema, and scarring during or after treatment. Strong pulsed light may have less adverse reactions. Weighing adverse reactions and effects, low-dose photodynamic therapy is more suitable for treating photoaging. Kosaka et al proposed that low concentration and short application time can reduce the incidence of photodynamic therapy adverse reactions. It is recommended to use 5% ALA for photodynamic skin rejuvenation and 2h for better application time.
Although several studies have demonstrated that photodynamic therapy can improve the skin barrier while treating photoaging, clinical photodynamic therapy has not been used alone to improve the treatment of skin barriers. However, in various treatment options for skin photoaging, solar keratosis and acne, photodynamic therapy has the added advantage of improving the skin barrier.

3. Study on the Mechanism of Photodynamic Therapy on Photoaging and Skin Barrier Function

Photodynamic therapy has significantly improved the wrinkles and relaxation of photoaging skin. At the microscopic level, it is mainly reflected in the remodeling of dermal collagen, especially type I and type III collagen. Both Marmur and Orringer confirmed at the ultrastructural level that the levels of dermal type I collagen and type III collagen were significantly increased after ALA-photodynamic therapy and correlated with improved appearance of photoaged skin. Bjerring uses 0. 5% of ALA was treated with IPL single photodynamic therapy at a dose of 7 J/cm2. After 72 hours, human skin was detected. It was found that after 15 minutes of application, the production of type III collagen in the illuminating group was increased by 208%, and after 3 hours of application, the illuminating group was type 3 Collagen production increased by 483%. In animal models, Park et al. showed that after UV irradiation, the collagen content of mice decreased, and the deposition of elastin-like degeneration substances increased; the collagen content increased from the second day to the 21st day after ALA-photodynamic therapy, elastin The content of the denaturing material is reduced. Lv et al. used photodynamic intervention in the establishment of photoaging animal models, and found that ALA-photodynamics can prevent photoaging in hairless mice. The application of two-photon microscopy to evaluate dermal collagen, photodynamic prevention intervention group not only increased collagen density And the arrangement of collagen fibers is also more uniform and smooth.
At the cellular level, fibroblasts are the main force in the production of collagen in the dermis, while fibroblasts in photoaged skin are reduced in their ability to proliferate and synthesize collagen due to exposure to a large amount of degraded collagen. The morphology of dermal fibroblasts after UV irradiation is expanded with swelling of the endoplasmic reticulum, and ALA-photodynamic therapy can normalize the morphology of dermal fibroblasts. Zhou et al. showed that ALA-photodynamics not only increased the level of photoaged fibroblast matrix metalloproteinase (MMP), but also induced oxidative damage and apoptosis of photoaging fibroblasts, and to some extent avoided Damage to normal fibroblasts. In addition, the effects of photodynamic therapy on the molecular level of fibroblasts have also been studied: Yong et al. conducted in vitro experiments on the molecular mechanism of photodynamic rejuvenation, and found that ALA-photodynamics not only enhances the activity and proliferation of fibroblasts, but also enhances I. Type of collagen is expressed, and the ERK pathway of fibroblasts is activated by the production of reactive oxygen species (ROS).
In addition, with the deepening of research on true epidermal interaction, more and more evidence indicates that photodynamic therapy can also act indirectly on dermal fibroblasts to promote collagen remodeling. Since photodegradation of partially degraded and fragmented collagen fibers in the skin inhibits collagen germination, MMP is essential for the hydrolysis of old collagen and the synthesis of new collagen. Early transient MMP3 elevation further degrades the already broken collagen. . Karrer et al. showed that ALA-photodynamics can not only directly induce the production of MMP in dermal fibroblasts, but also promote the synthesis of MMP by acting on fibroblasts by secreting soluble molecules in epidermal keratinocytes. Kim and other keratinocytes were subjected to low-dose ALA-photodynamic treatment, and the supernatant was used to stimulate fibroblasts, which increased the collagen production of fibroblasts and detected IL-1α, IL- in the supernatant. 6 and TNF-α levels are elevated, suggesting that ALA-photodynamics not only directly affects fibroblasts involved in collagen remodeling, but also indirectly through the involvement of epidermal keratinocytes.
The effect of photodynamic therapy on skin photoaging pigmentation may be caused by photodynamic effects, causing different degrees of apoptosis and necrosis of highly proliferating epidermal cells, and eventually the stains fade or disappear. Photodynamic therapy improves the water content of the stratum corneum, and the mechanism of transepidermal water loss rate has not been studied in depth, which may be related to the abnormalization of epidermal cells to make epidermal cells tend to normalize. In the treatment of solar keratosis, photodynamic therapy kills malignant keratinocytes through necrotic and apoptosis-related pathways, while Pp IX also accumulates in keratinocytes surrounding the lesion, and the sublethal photodynamic effect can be Promote the replacement of epidermal keratinocytes. Alternatively, abnormal keratinocytes can specifically absorb photosensitizers, produce photodynamic effects and eventually fall off, normal epidermal cells regenerate, dry and rough skin photoaging is alleviated, the “brick wall” structure of skin barrier is remodeled, and skin barrier function is restored. . Studies have shown that the skin thickness increases after MAL-PDT treatment, and the thickness of the hypoechoic band under the ultrasound is reduced, which means that the thickness of the epidermis is increased, which is conducive to strengthening the skin barrier. The mechanism may be related to photodynamic stimulation of normal epidermal keratinocyte regeneration.

4. Conclusion

Photodynamic therapy can improve the appearance of wrinkles and pigmentation of skin photoaging, and remove the skin precancerous lesions associated with photoaging, which is effective, and at the same time improves the water content of the stratum corneum and the rate of transepidermal water loss. There have been some studies on photosensitizers, light sources, concentrations, illuminating doses and efficacy in terms of therapeutic effects. However, the specific mechanism has not been fully elucidated, especially the research on skin barrier function is lacking, and further research is needed.